The liver is a vital organ whose functions include, among other things, detoxification, protein synthesis, maintaining an adequate supply of glucose and lipids to the surrounding tissues. R. Kahl's Chapter 13 entitled “The Liver,” pp. 273-296 in H. Marquardt's Toxicology (1999): Academic Press, San Diego, Calif. Chronic liver diseases such as hepatitis B virus and hepatitis C virus, liver cancer and certain metabolic diseases can seriously injure the liver. Serious liver injury can give rise to a loss of any one of certain liver functions, which in turn can lead to liver failure and death of the organism. Certain drugs that may be effective for treating identified liver diseases may cause unwanted and even serious side-effects that limit the drug's usefulness. Therefore, specific liver-targeting is an important consideration in developing a particular drug substance designed to combat certain liver diseases.
M. D. Erion in “Prodrugs for Liver-targeted Drug Delivery,” Biotechnology Pharmaceutical Aspects, 1, Volume V, Prodrugs, Part II, Part 5, Pages 541-572, explains that liver-utilization of certain nucleosides and/or nucleoside-analogs can be hampered if the drug substance is a poor substrate for certain phosphorylating enzymes generally known as kinases. The biological activity of some pharmaceutically active agents may be hampered by poor substrate characteristics for one or more of the kinases needed to convert it to the active triphosphate form or alternatively for introduction into a cell that requires treatment. Formation of the monophosphate by a nucleoside kinase is generally viewed as the rate limiting step of the three phosphorylation events. To circumvent the need for the initial phosphorylation step in the metabolism of an active to the triphosphate analog, the preparation of stable phosphate prodrugs has been reported. Nucleoside phosphoramidate prodrugs have been shown to be precursors of the active nucleoside triphosphate and to inhibit viral replication when administered to viral infected whole cells (McGuigan, C., et al., J. Med. Chem., 1996, 39, 1748-1753; Valette, G., et al., J. Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et al., Proc. National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q., et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg, E. J., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20, 1091-1098; Lee, W. A., et al., Antimicrobial Agents and Chemotherapy, 2005, 49, 1898; Mehellou, Y., et al. ChemMedChem., 2009, 4, 1779-1791); US 2006/0241064; and WO 2007/095269. Erion further proposes strategies for circumventing the kinase-associated problems. For instance, Erion identifies a prodrug variant of adefovir, which is designated chemically as (2R,4S)-2-(2-(6-amino-9H-purin-9-yl)ethoxy)-4-(3-chlorophenyl)-1,3,2-dioxaphosphinane 2-oxide, was designed to deliver an adefovir containing a phosphorus moiety to the liver. Erion discloses other strategies for delivering nucleosides and nucleoside-analogs to the liver, but does not disclose or suggest the phosphorus-containing actives.
Also limiting the utility of actives as viable therapeutic agents is their sometimes poor physicochemical and pharmacokinetic properties. These poor properties can limit the intestinal absorption of an agent and limit uptake into the target tissue or cell. To improve on their properties prodrugs of actives have been employed. It has been demonstrated in certain instances that preparation of nucleoside phosphoramidates improves the systemic absorption of a nucleoside and furthermore, the phosphoramidate moiety of these “pronucleotides” is masked with neutral lipophilic groups to obtain a suitable partition coefficient to optimize uptake and transport into the cell dramatically enhancing the intracellular concentration of the nucleoside monophosphate analog relative to administering the parent nucleoside alone. Enzyme-mediated hydrolysis of the phosphate ester moiety produces a nucleoside monophosphate wherein the rate limiting initial phosphorylation is unnecessary. This concept has been demonstrated for certain compounds disclosed in US 2010/0016251. There, certain 2′-deoxy-2′-α-F-2′-β-C-methyluridine phosphoramidates are capable of being absorbed through the intestinal tract, and then, delivered to the liver where the phosphoramidate moiety is cleaved to produce a 2′-deoxy-2′-α-F-2′-β-C-methyluridine monophosphate. It is conceivable that the liver-directed phosphoramidate approach can be applied to actives other than the above-mentioned 2′-deoxy-2′-α-F-2′-β-C-methyluridine phosphoramidates. Such an approach would leverage the ability of the liver to metabolize the phosphoramidate moiety to the monophosphate and in the case of a non-nucleoside to lose the phosphate group ultimately releasing the active agent.
However, a potential complicating factor is that asymmetrically-substituted phosphoramidates can exist as either enantiomeric or diastereomeric mixtures. These mixtures may be purified to afford enantiomerically- or diastereomerically-enriched compositions, but the additional purification can increase overall costs for production of the phosphoramidate-derivatized active. In an effort to reduce and/or eliminate the potential complicating factor, a methodology has been developed to prepare enantiomerically- or diastereomerically-enriched phosphoramidate reagents, which may then be used as useful starting materials for the preparation of enantiomerically- or diastereomerically-enriched phosphoramidate-containing actives.